Pharmaceutical medicaments and diagnostic compounds are frequently incorporated into a delivery vehicle for administration to a targeted tissue site. Typically, drug delivery vehicles are formed as aqueous carriers, gels, polymeric inserts or particulates incorporating a pharmaceutical compound. Once the drug delivery vehicle is placed at the desired delivery site, the pharmaceutical compound is released from the delivery vehicle over a period of time. The time release profile of the drug is dependent upon a number of variables. Included in these variables are the release mechanisms of the drug from the drug delivery vehicle (typically either erosion, diffusion or both), the amount of drug incorporated into the drug delivery vehicle, the solubility of the drug in the surrounding physiological milieu and, in the case of particulate delivery vehicles, the particle size or size distribution of the vehicle.
Depending upon the physical characteristics of the vehicle itself as well as those at the intended target site, drug delivery vehicles may be delivered to the target site through a variety of known routes of administration. For example, aqueous based drug delivery solutions may be ingested, injected, inhaled, or applied directly to the skin or mucus membranes as drops, mists, sprays or the like. Conversely, gels and ointments are better suited to direct topical application due to their high viscosities which prevent drop elimination. Similarly, solid polymeric inserts must be physically inserted or affixed to the target site.
A particularly unique target site for pharmaceutical compounds is the ocular environment surrounding the surface of the eye. Aqueous solutions, gels and solid inserts have all been utilized to deliver ocular drugs as the controlled delivery characteristics of such known delivery vehicles make them well suited for such purposes. Though easily administered as drops, tear turnover and drainage through the lacrimal system quickly remove a major portion of any drop administered compound so that only a small fraction of the original dosage remains in the eye long enough to be of therapeutic impact. Moreover, the high liquid dose volumes inherent in water and oil based drop delivery systems result in inefficient use of the drug delivery compositions. As a result, repeated administrations of the drug containing drops are required to maintain an effective therapeutic level of the drug in the eye. To combat these drawbacks, pharmaceutical compositions formulated as ointments, gels or inserts have been developed which remain in the eye longer and gradually release their diagnostic or therapeutic drugs into the ocular environment in order to reduce the need for repeated administrations. However, these compounds are difficult to deliver and may affect the patient's vision.
More recently, particulate drug delivery systems relying on drug microparticles, microcapsules or drug-containing erodible microparticles or microcapsules have been developed with some limited success. These microparticles or microcapsules are designed to be suspended in a liquid carrier medium and delivered to the target tissue through injection, ingestion or as liquid drops. Once at the target site the microparticulates or microcapsules are intended to remain at that location after the liquid carrier has diffused or drained away. Typically, microparticulates are formed of a drug or drug containing polymer matrix comprising particles ranging from tens to hundreds of microns in diameter. The polymer matrix may be erodible to release the incorporated drug at the target site as the matrix gradually breaks down. Alternatively, the microparticulates may be formed of nonerodible polymers from which the incorporated drug simply diffuses out of and into the target tissue. Microcapsules are comparably sized hollow particles formed of a polymer shell encapsulating the desired pharmaceutical compound. The shell of microcapsules may also be composed of either erodible or nonerodible polymers. Problems with particulate settling during storage and with particle retention after delivery have limited the utility of such compositions.
The long term storage of any liquid pharmaceutical compound requires a liquid carrier medium that is physically and chemically compatible with the incorporated therapeutic or diagnostic compound, with any associated particulate carrier and with the intended physiological target environment. Generally, the liquid carrier of choice is a sterile water solution of the appropriate pH and osmolality. However, a problem with mixing and storing pharmaceutical compounds in aqueous carriers intended for an aqueous physiological target environment is that invariably the particles will break down or dissolve or the incorporated pharmaceutical compound will leach out into the aqueous carrier prior to administration. This may result in a significant loss of pharmaceutical activity following administration as any released or leached drug contained in the aqueous carrier will be flushed from the target site relatively rapidly as the carrier is drained through the lacrimal system.
This tendency to break down or leach into the carrier also limits the effective shelf-life of drug delivery vehicles based upon aqueous carriers. Depending upon the dissolution or diffusion rate of the incorporated pharmaceutical compound, the shelf-life will normally be much shorter than the preferred shelf-life. As a related problem, diffusion of the drug into the aqueous carrier makes it difficult, if not impossible, to formulate multiple dose packaging because uniform dose regimens cannot be ensured over time.
Adding to these problems, a significant number of the drugs and the polymeric microparticulates currently being used are hydrolytically labile. This characteristic is central to their ability to slowly dissolve or to release the drug into the target aqueous physiological environment. Because drugs or polymers exhibiting hydrolytic instability cannot be stored in aqueous vehicles, they must be stored in a dry state and suspended in the aqueous carrier immediately prior to their administration to the target site. This is a time consuming and burdensome inconvenience to the end user. Moreover, it requires specialized packaging designs which provide a method for separately storing the labile drug or polymer particles and the sterile carrier liquid in appropriate quantities. As a result, the package configuration must be limited to unit dose sizes with the attendant inconvenience and added costs.
Several nonaqueous liquid carriers have been utilized in the art in an attempt to address these problems. Among these are mineral oils, vegetable oils, silicone oils, and free fatty acids. Though generally effective for oral and dermal administration, when used in the ocular environment a significant disadvantage associated with these oils is that they combine with, and disrupt, the lipid layer of the tear film which, in turn, may cause the user to experience significant vision blurring and an unacceptable oily sensation. Even if the tear film is not disrupted, the significant difference between the refractive index of the tear film and that of the oil carrier causes vision blurring during the residence time of the oil in the eye.
A related drawback associated with the drop instillation delivery of ophthalmic pharmaceuticals in water or oil carriers is that conventional eye droppers have relatively limited delivery volumes restricted to drop sizes that may interfere with vision or be uncomfortable to the user. This is because the density and surface tension characteristics of the typical water- or oil-based systems do not allow for the practical delivery of drops having less than 35 .mu.l volumes. Because the eye tear film can accommodate only about a 7 to 10 .mu.l volume of liquid without disruption or discomfort, when amounts greater than this are delivered to the eye the excess liquid will either disrupt the tear film or be rapidly blinked away. This results in the inefficient and costly loss of both liquid carrier and pharmaceutical agent and still requires repeated drop administration over unacceptably short intervals for therapeutic effectiveness.
In an attempt to overcome the problems associated with conventional oil-based drug delivery vehicles, other nonaqueous liquids such as perfluorocarbons have been used as carries. For example, European patent application no. 0 091 313 discloses the use of perfluorocarbon-based pharmaceutical compositions as drug delivery vehicles. While a substantial improvement over traditional oil or water based carriers, pharmaceutical compounds suspended in perfluorocarbon carriers have been found to settle out over time leading to particulate aggregation and to uneven dispersion of the drug within the carrier. Though the uniform dispersion of the drug can usually be reestablished through shaking or mixing, prolonged and repeated aggregation of the drug particulates can, in some cases, reduce the efficacy of the pharmaceutical composition and adversely shorten the shelf life. Further, insufficient mixing of the particulates with the carrier prior to administration can result in a non-homogeneous suspension and inconsistent dosages.
Accordingly, it is an object of the present invention to provide nonaqueous drug delivery vehicles for the administration of therapeutic or diagnostic pharmaceutical compounds which provide for the prolonged homogeneous suspension and uniform dispersion of the incorporated compounds
It is a further object of the present invention to provide effective high bioavailability pharmaceutical drug delivery compositions which promote the bioadhesion and retention of the incorporated drug onto the surface of the eye for extended periods.
It is yet a further object of the present invention to provide pharmaceutical compositions incorporating therapeutic or diagnostic pharmaceutical compounds which exhibit improved shelf lives and stability.
It is an additional object of the present invention to provide pharmaceutical compositions which may be administered to the eye using low dose volume drops, which remain in the eye as a comfortable, viscous composition.
It is yet an additional object of the present invention to provide pharmaceutical drug-delivery compositions for use in aqueous physiological systems which may be configured in multidose administration packaging.
It is yet another object of the present invention to provide pharmaceutical drug delivery compositions capable of forming drop sizes on the order of 10 .mu.l when delivered from standard dropper bottles.